Vascular complications of diabetes mellitus are the major cause of morbidity and mortality among diabetics today. The major objective of the research proposed in this application is to increase our understanding of the pathogenesis of diabetic vascular disease and to identify genetic markers which may aid in identifcation of individuals at increased risk of developing vascular complications. We will investigate interrelationships between diabetic microvascular disease (manifested by muscle capillary basement membrane thickening), increased vascular permeability (quantified in the eye by quantitative vitreous fluorophotometry), severity of diabetes (reflected in hemoglobin A1c levels), and serum haptoglobin levels and phenotype (determined by quantitative immunoelectrophoretic techniques). Other studies planned include: 1) examination of muscle capillary basement membrane in subjects with hereditary spherocytosis in order to determine whether decreased red cell deformability (which has been reported in diabetics) in the absence of diabetes can influence muscle capillary basement membrane width, 2) assessment of muscle capillary basement membrane thickening in subjects with diabetes secondary to cystic fibrosis of the pancreas, and 3) measurement of myocardial capillary basement membrane width in diabetics and in nondiabetics at autopsy to determine the relationship between capillary basement membrane thickening in skeletal muscle, heart and kidney.